Inhaled nisin as an emergency intervention against antibiotic sensitive or resist

描述(由申请人提供)：故意释放炭疽芽胞仍然是生物恐怖主义和生物武器方面的迫在眉睫的威胁。吸入这些孢子的人极有可能感染和死于炭疽热。目前对炭疽芽胞吸入的预防和治疗分为两类。接种疫苗以防止未来接触，以及抗生素治疗以治疗系统性细菌感染。市场上出售的炭疽疫苗需要在18个月内接种6剂才能完全有效，虽然已经有一些关于接触后接种的非临床研究，但这尚未被证明有助于预防疾病。抗生素治疗，通常使用环丙沙星，只有在吸入的孢子萌发并生长为营养细胞后才有效，此时会表达两种炭疽毒素。改造抗药性炭疽杆菌菌株使抗生素失效是可能的。炭疽杆菌的孢子本身是惰性的，在萌发和营养生长之前不会释放毒素，因此，有一种产品可以在萌发前中和吸入的孢子，从而使它们保持惰性，直到它们从体内清除出去，这将是非常有用的。抗菌肽Nisin具有独特的结合和中和细菌孢子的能力，包括炭疽杆菌孢子和从抗药性炭疽杆菌分离的孢子。通过与孢子表面结合，Nisin阻止了萌发过程。Nisin已获得FDA的“公认安全”称号，目前被广泛用作食品防腐剂，并用于各种局部兽药产品。这份意见书的目标是开发一种吸入型乳链菌素制剂，在接触吸入性炭疽孢子的情况下，可在常规抗生素和其他炭疽病疗法之外使用。这是唯一已知的可在紧急情况下使用的干预措施，可用于中和吸入的孢子。该产品将以一次性吸入器的形式与急救人员和军事人员一起部署，在疑似孢子吸入后立即使用，以便在发芽和产生毒素之前中和肺部吸入的孢子。这项提案将测试Nisin保护动物免受炭疽孢子肺部攻击的能力，并检查Nisin输送到肺部的安全性。与公共卫生相关：炭疽病仍然是一个严重的生物恐怖主义/生物武器威胁。炭疽芽孢杆菌的孢子相对容易产生和传播，而这种“武器化”的过程使这些孢子成为更有效的生物恐怖分子。从2001年的事件中吸取的教训之一是，故意接触炭疽孢子，特别是武器化孢子造成的感染可能非常难以治疗。在炭疽孢子攻击的情况下，接触孢子的受害者可以接受几种治疗，以试图阻止疾病的发展。目前的护理标准是长期服用抗生素，如环丙沙星或多西环素，最长可达60天。像BioThrax(紧急生物解决方案)这样的疫苗也可以在接触后立即接种，希望产生一些保护性免疫，但这种疫苗需要在18个月内接种6剂才能完全保护。目前，还没有专门设计的产品来中和呼吸道中的孢子。炭疽孢子是炭疽杆菌的感染体，但它们本身是惰性的，不具致病性。这些孢子必须萌发并营养生长才能表达毒素，能够中和肺部被吸入的孢子并阻止它们的萌发可能有助于预防疾病。最好的是，这种中和剂可以防止所有孢子的萌发，但即使中和一定比例的孢子，也会给其他疗法带来更好的成功机会。目前迫切需要一种专门为中和呼吸道中的炭疽孢子而设计的产品。这种产品应该是极其安全的，并且能够以这样的方式在现场使用，即在怀疑炭疽孢子暴露是除使用抗生素、暴露后疫苗和正在开发的其他疗法之外的额外保护层的情况下和在医院使用。本意见书建议开发一种吸入性产品，该产品可以在吸入的炭疽孢子萌发和生长导致系统性和致命性疾病之前中和它们。本产品旨在作为其他炭疽病治疗方法的补充。目前还没有这样的产品可用。

DESCRIPTION (provided by applicant): The deliberate release of Bacillus anthracis spores remains an imminent threat both in terms of bioterrorism and biowarfare. Individuals who inhale these spores are at extreme risk of infection and death from anthrax. Current prophylaxis and therapy in the event of B. anthracis spore inhalation fall into two categories. Vaccination to protect against future exposure, and antibiotic therapy to treat systemic bacterial infections. The commercially available anthrax vaccine requires 6 doses over 18 months for full efficacy and while there have been some non-clinical studies of post exposure vaccination, this has not yet been proven to be helpful for prevention of disease. Antibiotic therapy, usually with ciprofloxacin, is effective only after the inhaled spores germinate and grow as vegetative cells, at which time two anthrax toxins are expressed. It is possible to engineer antibiotic resistant strains of B. anthracis that would render antibiotics ineffective. B. anthracis spores themselves are inert and do not express toxin until they germinate and grow vegetatively, thus it would be of great utility to have a product which could neutralize inhaled spores prior to germination thus keeping them inert until they can be cleared from the body. The lantibiotic peptide nisin has the unique capacity to bind to and neutralize bacterial spores, including B. anthracis spores and spores isolated from antibiotic-resistant B. anthracis. By binding to the spore surface, nisin arrests the germination process. Nisin has received a "Generally Recognized As Safe" designation from the FDA, is currently widely used as a food preservative, and is used in various topical veterinary products. The goal of this submission is to develop an inhaled nisin formulation that could be used in addition to conventional antibiotics and other anthrax therapies in the event of exposure to inhaled anthrax spores. It is the only know intervention that can be used on an emergency basis to neutralize inhaled spores. This product would be deployed with first responders and military personnel in the form of a disposable inhaler to be used immediately after suspected spore inhalation to neutralize the inhaled spores in the lungs prior to germination and toxin production. This proposal will test the capacity of nisin to protect animals against pulmonary challenge with anthrax spores and examine the safety of nisin delivery to the lungs. PUBLIC HEALTH RELEVANCE: Anthrax remains a serious bioterrorism/biowarfare threat. Spores of Bacillus anthracis are relatively easy to produce and disseminate, and the "weaponization" process makes these spores even more effective bioterrorism agents. One of the lessons learned from the events of 2001 is that infections resulting from deliberate exposure to anthrax spores, especially weaponized spores, can be very difficult to treat. In the event of an attack with anthrax spores, victims exposed to the spores can receive several treatments to try to prevent disease progression. The current standard of care is long term dosing of antibiotics like ciprofloxin or doxycycline which can be administered for as long as 60 days. Vaccines, like Biothrax (Emergent Biosolutions) can also be administered immediately after exposure with the hope of generating some protective immunity, but this vaccine requires six doses over eighteen months to be fully protective. Currently, there are no products specifically designed to neutralize spores in the respiratory tract. Anthrax spores are the infectious agent of B. anthracis, but by themselves are inert and not pathogenic. The spores must germinate and grow vegetatively to express toxins, and being able to neutralize inhaled spores in the lungs and prevent their germination could help prevent disease. Optimally, such a neutralizer, which prevent the germination of all spores, but neutralization of even a percentage of the spores would give the other therapies a better chance for success. There is an immediate need for a product specifically designed to neutralize anthrax spores in the respiratory tract. This product should be extremely safe and be able to be formulated in such a way that it can be used in the field in situations and in hospitals where anthrax spore exposure is suspected as an additional layer of protection beyond the use of antibiotics, post exposure vaccinations and other therapies in development. This submission proposes to develop an inhaled product that can neutralize inhaled anthrax spores before they germinate and grow to cause systemic and fatal disease. This product is intended as an addition to other anthrax therapies. Currently there is no such product is available.